Background

Second malignant neoplasms are the leading cause of death among long-term survivors of Hodgkin lymphoma (HL) (Hoppe et al. Ann Oncol, 1997).

Breast cancer (BC) is the most common solid tumor diagnosed among female HL survivors.

The markedly increased risk of BC among women receiving chest radiotherapy for HL is well established in the literature.

Risk of BC in HL survivors appears to be inversely related to age at diagnosis once adolescence is reached, and has been directly correlated with radiation dose to the chest wall (Travis et al. JAMA, 2003)

Published models of BC risk for a woman under the age of 25 treated for HL receiving >
40 Gy chest wall dose estimate a 29.0% risk of BC by age 55 (Travis et al. JNCI, 2005)

Despite these well-recognized concerns, there are no large population-based studies that describe BC related outcomes in patients who are long term survivors of HL compared to women with a first primary BC.

Methods

This study was a retrospective cohort study that used data from the Surveillance, Epidemiology, and End Results program, a population based cancer registry sponsored by the NCI.

The authors hypothesized that BC related outcomes would be worse among HL survivors compared to women with a first primary BC. Their rationale for this hypothesis was that prior cancer related treatment in HL survivors could potentially limit therapeutic options for BC, and that genomic instability induced by prior therapy could also be associated with development of additional malignancies in these patients

The authors identified 9,946 patients in the SEER database with a history of HL, of whom 298 (2.9%) developed BC (HL-BC patients)

The comparison group for the study was made up of 405,223 women with a first or only BC (BC-1 patients).

All patients were grouped by BC stage and were then dichotomized as either having localized disease, or regional/distant disease.

An actuarial age-adjusted survival analysis was used to calculate overall survival (OS) and cancer specific survival (CSS) for the two groups.

A Cox multivariate analysis was used to compare survival outcomes between the two groups adjusting for age, BC stage, hormone receptor status, sociodemographic status, radiation for HL, and other variables.

Results

In the HL-BC patient group, the median latency between HL diagnosis and BC diagnosis was 15.2 years

Compared with BC-1 patients, the HL-BC patients were significantly younger at the time of BC diagnosis (45 vs. 61 years old, p < 0.0001).

HL-BC patients were > 1.5 times (p
< 0.0001) more likely to undergo mastectomy (rather than breast conserving surgery) compared with BC-1 patients, and were > 2 times (p < 0.0001) less likely to have received radiation than BC-1 patients.

10-year BC CSS was similar for HL-BC and BC-1 patients with regional/distant disease, but was inferior for patients with localized BC (82% vs. 88% respectively (p = 0.002).

Authors' Conclusions:

Women with a history of HL have an increased risk of BC, and their oncologic outcomes, including overall survival and cancer specific survival, appear to be worse than those of women with a primary diagnosis of breast cancer.

HL-BC patients may survive a diagnosis of BC only to experience significant excesses of death from additional cancers and/or cardiac disease.

Greater awareness of screening for cardiac disease and subsequent cancers in HL-BC patients is warranted.

Clinical Implications

Second malignancies are the leading cause of death among long-term survivors of HL, and female survivors of HL have a markedly increased risk of BC.

The authors found that female HL survivors subsequently diagnosed with BC are more likely to have aggressive breast cancers, and that their cancer specific outcomes are inferior to population based controls.

The study was well conducted and utilized an elegant statistical methodology to control for confounding covariates between the two patient groups.

The strengths of the study include the large number of patients included in the study and the long follow-up available for these patients in the SEER registry data.

The limitations of the study are primarily related to inherent limitations of the SEER registry data and include:

Lack of information about administration of chemotherapy for these patients.

Lack of complete information about hormone receptor status for these patients as this information was only more recently included in SEER.

Lack of complete information regarding cardiac disease -- the analysis of cardiac disease in these patients is limited only to cardiovascular mortality as SEER does not record development of non-fatal cardiac disease.

This study highlights the importance of long term follow-up after treatment for HL, and the need for aggressive cancer screening and cancer prevention in this high-risk patient group. Current cooperative group recommendations include MRI-based screening for breast cancer in patients who have had previous chest wall radiation, and the results of this study support these recommendations.

Additionally, the observed increased risk of cardiovascular mortality in HL-BC patients supports the need for preventive measures such as healthy lifestyle counseling, and smoking cessation interventions.